Lutathera is recently FDA-approved (approval Jan 26, 2018) as a single agent treatment for use in GEP-NET. Lutathera has been shown to have efficacy in GEP-NET via the Phase III NETTER-1 trial (Strosberg et al. NEJM 2017, 376;2), which demonstrated improved PFS at 20 months from 10.8% to 65.2%, and decreased deaths from 26 in the control group to 14 in the treatment group. It's mechanism of action is receptor-targeting by DOTA-TATE (which is an octreotide analogue) to the somatostatin receptor (predominantly SSTR-2) that is known to be over-expressed on GEP-NET cells. The active ingredient of the agent is Lutetium-177, which is a radioactive molecule that is chelated to DOTA-TATE and emits beta-particle radiation which kills cancer cells via inducing single-stranded DNA breaks. Given the mechanism of action of these agents, it is reasonable that one would see synergy when combining a PARP-inhibitor with radioactivity. There has been a number of published pre-clinical studies which demonstrated the radiosensitization effects of PARP-inhibitors in rodents and in human cell lines (Figure 1). There has also been previous work specifically looking at olaparib as a radiosensitizer. In one such study (Verhagen et al. Radiotherapy and Oncology 2015, 116:358-365), it was found that 7 hours of exposure to olaparib was sufficient to have a radiosensitizing effect. Furthermore, the extent of radiosensitization is dose dependent, and that the doses needed to achieve radiosensitization is much lower than that needed for single agent activity (on average 30 fold less). Specifically for olaparib and Lutathera, pre-clinical studies done with live human GEP-NET tumor slices (Nonnekens et al. Theranostics 2016, 6;11) demonstrated significant radiosensitization effects of olaparib. Among other findings, the surviving cell fraction after treatment with the combination is significantly less compared to either single agent treatments and to control (Figure 1), likely due to the conversion of unrepaired single-stranded DNA breaks to more lethal double-stranded breaks (Figure 2). The primary toxicity (SAE) of olaparib is hematologic, primarily anemia. Lutathera is generally well tolerated with primary SAE toxicity of lymphopenia (9%), thrombocytopenia (2%), and GI disturbances such as nausea (4%) and vomiting (7%) (Figure 4). As there is potential for overlapping myelotoxicity, a careful dose escalation Phase 1 study using the 3+3 design is included in the proposal where Lutathera will be given at full-dose (200 mCi), with olaparib being started at 50mg bid then ramped up by 50mg each dose level up to 400mg bid as tolerated, with weekly CBC checks. Alternatively, to expedite the Phase I portion of the trial, we can start at 100mg bid and dose escalate by 100mg per cohort up to 400mg bid. Hypothesis 1. The combination of olaparib + Lutathera can be used safely in humans. 2. Olaparib will act as an radiosensitizer when used in combination with Lu-177-DOTATATE, achieving a combinational efficacy that is greater than either agent alone. Primary objective 1. Phase I: Characterize the safety profile and tolerability of the olaparib + Lutathera combination, using the 3+3 dose escalation design; determin the MTD dose of the combination 2. Phase 2: Determine the PFS of GEP-NET patients treated with the combination as determined by RECIST 1.1 Secondary objective - Response rate, overall survival rate, quality of life assessments between control vs. combination arms - Use of Gallium-68-DOTATATE PET scans (FDA approved to image somatostatin-receptor positive tumors) for response evaluation in GEP-NET - Examine potential serum biomarkers of response to therapy in GEP-NET such as micro-RNA Treatment regimen 1. Phase I: full dose of Lutathera (200 mCi) + escalating dose of olaparib, starting at 50mg bid, then 100mg bid, 200mg bid, up to 300mg bid or MTD, whichever comes first 2. Olaparib at MTD + Lutathera (200 mCi) Inclusion criteria - histologically proven GEP-NET - inoperable disease (metastatic, non-surgical candidates, locally advanced into vessels or other critical structures) -Age 18+ -at least one Ga68-DOTATATE positive lesion Exclusion criteria - hg less than 8, LFT greater than 2.5x ULN, plt les than 100, WBC less than 2.0 or ANC less than 1,000 - creatinine greater than 1.7 - other co-existing malignancies unless definitively treated Primary endpoint 1. Phase 1: safety of combination, MTD 2. Phase 2: PFS by RECIST 1.1 Secondary endpoint - Response rate, overall survival rate, quality of life assessments between control vs. combination arms - Use of Gallium-68-DOTATATE PET scans (FDA approved to image somatostatin-receptor positive tumors) for response evaluation in GEP-NET - Examine potential serum biomarkers of response to therapy in GEP-NET such as micro-RNA Correlative studies - Use of Gallium-68-DOTATATE PET scans (FDA approved to image somatostatin-receptor positive tumors) for response evaluation in GEP-NET - serum microRNA studies in GEP-NET - metabolomics studies Sample size justification/statistical analysis -Phase I: data for the phase I objective will be reported descriptively; therefore no formal statistical sample size calculation was done. Depending on what the speed of dose escalation and the final MTD dose, it is estimated that approximately 12 to 36 patients will be required for the phase I portion of the study. Standard 3+3 design will be used. -Phase II: The primary objective of the Phase II portion is to obtain preliminary evidence of efficacy of the combination at the Phase I recommended dose. The sample size and interim stopping rule will be determined using a Simon optimal two-stage design. A response rate of 15% for the Lutathera+Olaparib combination treatment would be considered not promising, while a 30% response rate would be considered promising. With alpha=0.10 and beta=0.20, 19 patients will be accrued to the study in the first stage. If 3 or fewer patients demonstrate response, the accrual to the study will be terminated early and the trial declared to have a negative result. A pause in the accrual may be necessary to ensure that enrollment may continue to the second stage. If 4 or more patients demonstrate response, enrollment will be extended to accrue a total of 39 patients. If 4-8 respond to therapy, this will be considered insufficient to warrant further study, while if 9 or more of 39 patients respond to therapy, the treatment will be declared effective and worthy of further testing. Under the null hypothesis (15% response rate), the probability of early termination is 68%.